Cabozantinib alone or in combination with erlotinib extended survival compared with erlotinib alone.

  • Major finding: Cabozantinib alone or in combination with erlotinib extended survival compared with erlotinib alone.

  • Approach: The safety and activity of cabozantinib was evaluated in a controlled, open-label phase II trial.

  • Impact: Patients with advanced EGFR–wild-type NSCLC may respond to cabozantinib alone or with erlotinib.

EGFR mutations occur in approximately 15% of patients with non–small cell lung cancer (NSCLC), and these patients respond to treatment with the EGFR inhibitor erlotinib. Erlotinib has also been shown to extend survival in patients with EGFR–wild-type NSCLC, and is thus used as a second-line or third-line therapy. Acquired resistance to EGFR inhibitors can occur via MET amplification, and preclinical studies have suggested that MET inhibition may synergize with EGFR inhibition. Neal and colleagues evaluated the safety and efficacy of cabozantinib, a multikinase inhibitor with activity against MET, alone, in combination with erlotinib, and compared with erlotinib alone in an open-label phase II clinical trial in patients with advanced EGFR–wild-type NSCLC. In total, 111 eligible patients received treatment; 38 received erlotinib alone, 38 received cabozantinib alone, and 35 received erlotinib plus cabozantinib. The primary endpoint was progression-free survival, and secondary endpoints included toxicity and exploratory studies to identify predictive biomarkers of response. The median progression-free survival was 1.8 months for patients treated with erlotinib alone, 4.3 months for patients treated with cabozantinib alone, and 4.7 months for patients treated with erlotinib plus cabozantinib, indicating that cabozantinib alone or in combination was more effective than erlotinib. MET expression was not a predictor of progression-free survival, suggesting that inhibition of other cabozantinib targets may contribute to the observed clinical benefit. Cabozantinib had a manageable tolerability, although cabozantinib treatment alone or with erlotinib was associated with more frequent grade 3/4 adverse events than erlotinib alone. Taken together, the results of this phase II study show that cabozantinib alone or in combination with erlotinib has an acceptable tolerability and superior efficacy compared to erlotinib alone, despite the added toxicity. These findings support the further study of cabozantinib-based regimens in patients with EGFR–wild-type NSCLC.

Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, et al. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol 2016 Nov 4 [Epub ahead of print].